The present invention relates to condensed thiophene compounds useful for the treatment of schizophrenia, Alzheimer""s disease, manic-depressive illness and the like, pharmaceutical use thereof and a synthetic intermediate thereof.
Schizophrenia is a mental illness having a high incidence of about 1% of the entire population. In most cases, convalescence is inferior and patients and their families are forced to suffer from a great burden over a long period of time. To avoid this, many studies have been done as to the etiology of schizophrenia, development of therapeutic drugs thereof and the like.
The first hypothesis proposed on the etiology of schizophrenia was an excess dopamine hypothesis. Based on this hypothesis, various compounds having a dopamine receptor inhibitory action have been developed as antipsychotic agents and achieved certain therapeutic effects.
The conditions of schizophrenia include positive symptoms mainly showing delusion, hallucination and the like, negative symptoms mainly showing social withdrawal, emotional torpor and the like, recognition function disorder such as defects of memory, learning disability and the like, and the like. A so-called typical antipsychotic agent centering on inhibition of dopamine receptor is comparatively effective on positive symptoms but ineffective against negative symptoms and recognition function disorders. When a typical antipsychotic agent is used, extrapyramidal side effects (e.g., dystonia, akathisia, delayed dyskinesia and the like) are inevitably caused by the dopamine receptor inhibitory action. These difficulties suggest a limit on the development of antipsychotic agent based solely on a so-called excess dopamine hypothesis.
In an attempt to solve the above-mentioned problems, antipsychotic agents, namely, serotonin-dopamine antagonist (SDA), having a serotonin receptor inhibitory action as a main action, have been studied and developed instead of dopamine receptor inhibitory action. Representative antipsychotic agents of SDA include risperidone, Seroquel and the like. However, the problems of poor effectiveness against negative symptoms and recognition function disorder or extrapyramidal side effects have not been entirely overcome [American Journal of Psychiatry 151, 825 (1994)].
One of the etiologic hypotheses of schizophrenia that have overtaken the excess dopamine hypothesis and the serotonin/dopamine hypothesis is a functional depression of glutamic acid nerve hypothesis [Trends in Neuroscience 13, 272 (1990)]. This hypothesis has been supported by the facts that (1) phencyclidine (PCP) which is an inhibitor of NMDA (N-methyl-D-aspartic acid) receptor induces mental conditions in human that are similar to schizophrenia with positive symptoms and negative symptoms [American Journal of Psychiatry 135, 1081 (1978), ibid. 148, 1301 (1991)], (2) cerebral cortex of schizophrenia patients shows lower reactivity of glutamic acid nervous system [Neuroscience Letters 121, 77 (1991)], (3) the number of NMDA receptors also present in the glutamic acid nervous system shows compensatory increase [Life Science 55, 1683 (1994)], (4) NMDA receptor agonists, such as glycine, D-cycloserine and the like, are effective for ameliorating the negative symptoms of schizophrenia [British Journal of Psychiatry 169, 610 (1996), American Journal of Psychiatry 152, 1213 (1995), ibid. 151, 1234 (1994)], and the like.
Clozapine and olanzapine are atypical antipsychotic agents characterized by their effectiveness against positive symptoms as well as negative symptoms of schizophrenia [Psychopharmacology 63,51 (1992), Neuropsychopharmacology 14, 111(1996)]. These atypical antipsychotic agents suppress abnormal behaviors induced in test animals [Psychopharmacology 120, 67 (1995), ibid, 129, 79 (1997), Pharmacology, Biochemistry and Behavior 47, 579 (1994)] and abnormal physiological function [Psychopharmacology 111, 339 (1993), Journal of Pharmacology and Experimental Therapeutics 271, 787 (1994)] by the functional depression of the glutamic acid nervous system by NMDA receptor inhibitors such as PCP and MK-801 (dizocilpine maleate), and their inhibitory capability is frequently stronger than that of typical antipsychotic agents. In other words, the superior clinical effects of the atypical antipsychotic agent may be ascribed to amelioration of functional depression of glutamic acid nervous system in addition to conventional dopamnine receptor inhibitory action and serotonin receptor inhibitory action.
The neurophysiological function abnormalities induced by an NMDA receptor inhibitor includes NMDA receptor inhibitor-induced neurotoxicity [Archive of General Psychiatry 52, 998 (1995)], and MK-801-induced neurotoxicity has been studied profoundly. This neurotoxic action can be inhibited by varioius antipsychotic agents, wherein the inhibitory action is stronger in clozapine and olanzapine that are atypical antipsychotic agents than in haloperidol and the like that are typical antipsychotic agents [Schizophrenia Research 15, 57 (1995), ibid. 21, 33 (1996)]. Using this MK-801-induced neurotoxic action as an index, an antipsychotic agent having an ameliorating action of functional depression of glutamic acid nervous system, that is one of the characteristics of clozapine and olanzapine, can be screened for. In addition, an MK-801-induced neurotoxic action is also considered a model of recognition function disorder observed in various diseases such as Alzheimer""s disease and the like [Brain Researchxe2x80x94Brain Research Reviews, 20, 250-267 (1995)], and a compound capable of inhibiting this neurotoxicity is also effective as a therapeutic drug of Alzheimer""s disease, manic-depressive illness and the like.
Meanwhile, the use of clozapine is limited, since it induces serious agranulocytosis, thougn it also shows superior antipsychotic action [New England Journal of Medicine 324, 746 (1991)]. Reduction of the possibility of side effects is also an important aspect in developing an antipsychotic agent. A report has been recently documented that a cation radical generated as a metabolitic intermediate of clozapine may be involved in the mechanism of onset of agranulocytosis [CNS-Drugs 7, 139 (1997)]. It is significant, therefore, to inhibit generation of cation radical to avoid the onset of agranulocytosis.
Heretofore, there are various reports on suitable modification of the chemical structures of clozapine and olanzapine. For example, WO95/17400, WO96/18621, WO96/18623, WO96/18629, WO96/18630 and WO96/19479 disclose dibenzoxazepine compound, Japanese Patent Examined Publication Nos. 42-24513, 42-24514, 43-27404, 45-20909, 45-6822, 46-29861, 48-34599 and 49-40236, and Japanese Patent Unexamined Publication No. 47-4425 disclose dibenzoxazepine or dibenzothiazepine compound, WO93/07143 discloses pyridobenzoxazepine compound, Journal of Heterocyclic Chemistry 31, 1053 (1994) discloses thienobenzoxazepine compound, and Japanese Patent Unexamined Publication No. 63-8378 discloses dibenzothiazapine compound.
In addition, benzothiophene compound is disclosed in, for example, Japanese Patent Unexamined Publication Nos. 52-87196 and 51-76296 with regard to 1,2,3,4-tetrahydrobenzothieno[2,3-b][1,5]benzodiazepine derivative.
However, these compounds have remotely overcome the problems of effectiveness against negative symptoms and recognition function disorder, extrapyramidal side effects and the like, and activation of function of glutamic acid nervous system of the compounds of clozapine and olanzapine having suitably modified chemical structures has not been reported.
The present inventors took note of the glutamic acid nervous functional depression hypothesis, and conducted intensive studies in an attempt to develop a compound which ameliorates positive symptoms as well as negative symptoms of schizophrenia and recognition function disorder, and which is free of serious side effects such as extrapyramidal disorders, agranulocytosis and the like. As a result, it has been found that the condensed thiophene compound of the formula (I) has superior dopamine receptor inhibitory action and glutamic acid nervous system function depression-ameliorating action, shows anti-methamphetamine action, anti-apomorphine action, conditioned avoidance response inhibitory action, MK-801-induced neurotoxicity inhibitory action, MK-801 discrimination antagonistic action, clozapine discrimination generalization action and the like in test animals such as mouse, rat and the like, and is useful as an antipsychotic agent; that the compound shows less side effects in the extrapyramidal system, such as catalepsy induction and the like; and that a reaction intermediate corresponding to the cation radical intermediate considered to cause agranulocytosis induced by clozapine was not detected when the reaction intermediate was analyzed by an ESR spectrum, using oxydation of the compound of the formula (I) by horseradish peroxidase as a model reaction of the metabolitic reaction of this compound, which resulted in the completion of the present invention.
It is therefore an object of the present invention to provide a condensed thiophene compound useful as a therapeutic agent for schizophrenia and the like and an important synthetic intermediate therefor. The condensed thiophene compound of the formula (I) is also useful as a therapeutic agent for Alzheimer""s disease and manic-depressive illness.
Accordingly, the present invention provides the following.
(1) A condensed thiophene compound of the formula (I) 
wherein
Ra and Rb are the same or different and each is hydrogen, alkyl, cycloalkyl, acyl, alkenyl, aryl, heteroaryl, aralkyl, alkoxy, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, acyloxyalkyl, acylaminoalkyl, halogen, alkyl halide or nitro, or Ra and Rb in conjunction may form a benzene ring or cyclohexene ring optionally having substituents R1, R2 wherein R1, R2 are the same or different and each is hydrogen, alkyl, alkoxy, hydroxyl or halogen;
X is NH, O, S, SO, SO2 or N-R4 wherein R4 is alkyl, provided that when X is NH, Ra and Rb in conjunction form a benzene ring optionally having substituents R1, R2, and when X is S, SO or SO2, Ra and Rb in conjunction form a benzene ring or cyclohexene ring optionally having substituents R1, R2;
ring A is a benzene ring having 1 to 4 the same or different substituents thereon selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, halogen, alkyl halide, nitro, amino, monoalkylamino, dialkylamino, acylamino, hydroxyl and cyano or a benzene ring without a substituent; and
R3 is a grou of the formula (1), formula (2), formula (3), formula (26), formula (27), formula (28), formula (29) or formula (30) 
xe2x80x83in the formula (1), formula (26), formula (27) and formula (30), R5, R6 and R7 are the same or different and each is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, amninoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl and a is an integer of 2-4, in the formula (2) and formula (28), R8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoallyl, monoalkylaminoalkyl, dialkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl, b is 1 or 2,
provided that the combination of X is O and R8 is aralkyl is excluded and when X is O, alkyl of alkyl, hydroxyalkyl or alkoxyalkyl at R8 has 1 to 4 carbon atoms, in the formula (3) and formula (29), R9 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl,
or a pharmaceutically acceptable salt thereof or a hydrate thereof.
(2) The condensed thiophene compound of (1) above, wherein the formula (I) is formula (IA) 
wherein
X is NH, O, S, SO, SO2 or N-R4 wherein R4 is alkyl;
R1 and R2 are the same or different and each is hydrogen, alkyl, alkoxy, hydroxyl or halogen;
ring A is a benzene ring having 1 to 4 the same or different substituents thereon selected from the group consisting of alkyl, cycloalktyl, alkoxy, alkoxyalkyl, halogen, alkyl halide, nitro, amino, monoalkylamino, dialkylamino, acylamino, hydroxyl and cyano or a benzene ring without a substituent;
ring B is a benzene ring wherein the bond shown by a dotted line and a solid line is a double bond or a cyclohexane ring wherein said bond is a single bond, provided that when X is NH, the bond shown by a dotted line and a solid line is not a single bond; and
R3 is a group of the formula (1), formula (2), formula (3), formula (26), formula (27), formula (28), formula (29) or formula (30) 
xe2x80x83in the formula (1), formula (26), formula (27) and formula (30), R5, R6 and R7 are the same or different and each is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyallyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl and a is an integer of 2-4, in the formula (2) and formula (28), R8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl, b is 1 or 2,
in the formula (3) and formula (29), R9 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl,
or a pharmaceutically acceptable salt thereof or a hydrate thereof.
(3) The condensed thiophene compound of (2) above, wherein the ring B is a benzene ring wherein the bond shown by a dotted line and a solid line is a double bond, or a pharmaceutically acceptable salt thereof or a hydrate thereof.
(4) The condensed thiophene compound of (2) above, wherein X is NH, O or S, R1 and R2 are the same or different and each is hydrogen, halogen, alkoxy or alkyl, the ring A is a benzene ring having 1 to 4 the same or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent, the ring B is a benzene ring wherein the bond shown by a dotted line and a solid line is a double bond, and R3 is a group of the formula (2) wherein R8 is hydroxyalkoxyalkyl, methyl or ethyl and b is 1, or a pharmaceutically acceptable salt thereof or a hydrate thereof.
(5) The condensed thiophene compound of (2) above, wherein X is NH, R1 and R2 are the same or different and each is hydrogen, halogen, alkoxy or alkyl, the ring A is a benzene ring having 1 to 4 the same or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent, the ring B is a benzene ring wherein the bond shown by a dotted line and a solid line is a double bond, and R3 is a group of the formula (2) wherein R8 is methyl or ethyl and b is 1, or a pharmaceutically acceptable salt thereof or a hydrate thereof.
(6) The condensed thiophene compound of (2) above, which is a member selected from the group consisting of
12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5benzodiaze,
8-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
8-chloro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
8-bromo-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
9-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
9-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
9-chloro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
9-bromo-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
9-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5,]benzodiazepine,
8,9-difluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
8,10-difluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
3-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
8-fluoro-3-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b ][1,5]benzodiazepine,
2-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
8-fluoro-2-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
3-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
8-fluoro-3-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine
8,9-dichloro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
7,8-dichloro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
3-bromo-8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
3-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
3-chloro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
1-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
4-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
3,8-difluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
3-fluoro-8-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine and
12-(4-ethylpiperazin-1-yl)-8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine
or a pharmaceutically acceptable salt thereof or a hydrate thereof.
(7) A pharmaceutical agent comprising a condensed thiophene compound of formula (IA) or a pharmaceutically acceptable salt thereof or a hydrate thereof, a pharmaceutical composition comprising said compound and a pharmaceutically acceptable additive, and an antipsychotic agent comprising, as an active ingredient, a compound of the formula (IA).
(8) A benzothiophene compound of the formula (IIA) 
wherein X is NH, O, S, SO, SO2 or N-R4 wherein R4 is alkyl, R1 and R2 are the same or different and each is hydrogen, alkyl, alkoxy, hydroxyl or halogen, ring A is a benzene ring having 1 to 4 the same or different substituents thereon selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, halogen, alkyl halide, nitro, amino, monoalkylamino, dialkylamino, acylamino, hydroxyl and cyano or a benzene ring without a substituent, and ring B is a benzene ring wherein the bond shown by a dotted line and a solid line is a double bond or a cyclohexane ring wherein said bond is a single bond, provided that when X is NH, the bond shown by a dotted line and a solid line is not a single bond, which is an important intermediate for the synthesis of the of compound of the formula (IA).
(9) A benzothiophene compound of (8) above, wherein X is NH, O or S, R1 and R2 are the same or different and each is hydrogen, halogen, alkoxy or alkyl, the ring A is a benzene ring having 1 to 4 the same or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen, hydroxyl and alkyl halide, or a benzene ring without a substituent, and the ring B is a benzene ring wherein the bond shown by a dotted line and a solid line is a double bond or a cyclohexane ring wherein said bond is a single bond, provided that when X is NH, the bond shown by a dotted line and a solid line is not a single bond.
(10) The benzothiophene compound of (8) above, which is a member selected from the group consisting of
6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
8-chloro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
8-bromo-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
8-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
9-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
9-chloro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
9-bromo-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
9-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
9-methoxy-6H-[1 ]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
8,9-difluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
3-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
8-fluoro-3-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
3-methoxy-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
8-fluoro-3-methoxy-6H-1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
2-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
8-fluoro-2-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
3,9-dimethyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one,
1,2,3,4-tetrahydro-8-methyl-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one,
8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one,
[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one,
8-methyl-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one,
8-fluoro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one,
1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one,
1,2,3,4-tetrahydro-8-methyl-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one,
8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one,
[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one,
8-methyl-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one,
8-fluoro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one,
8,9-dichloro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
7,8-dichloro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
9-trifluoromethyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
3-bromo-8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
6-methyl-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
3-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
3-chloro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
1-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
4-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11 H)-one,
3,8-difluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one and
3-fluoro-8-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H )-one.
(11) The condensed thiophene compound of (1) above, wherein the formula (I) is formula (IB) 
wherein
Raxe2x80x2 and Rbxe2x80x2 are the same or different and each is hydrogen, alkyl, cycloalkyl, acyl, alkenyl, aryl, heteroaryl, aralkyl, alkoxy, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, acyloxyalkyl, acylaminoalkyl, halogen, alkyl halide or nitro, and
ring A is a benzene ring having 1 to 4 the same or different substituents thereon selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, halogen, alkyl halide, nitro, amino, monoalkylamino, dialkylamino, acylamino, hydroxyl and cyano or a benzene ring without a substituent; and
R3 is a group of the formula (1), formula (2), formula (3), formula (26), formula (27), formula (28), formula (29) or formula (30) 
xe2x80x83in the formula (1), formula (26), formula (27) and formula (30), R5, R6 and R7 are the same or different and each is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl and a is an integer of 2-4, in the formula (2) and formula (28), R8 is hydrogen, alkyl having 1 to 4 carbon atoms, cycloalkyl, hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl wherein alkyl having 1 to 4 carbon atoms is substituted by alkoxy, and b is 1 or 2,
in the formula (3) and formula (29), R9 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acyl, alkoxycarbonyl or alkoxyalkyl,
or a pharmaceutically acceptable salt thereof or a hydrate thereof.
(12) The condensed thiophene compound of (11) above, wherein Raxe2x80x2 and Rbxe2x80x2 are the same or different and each is hydrogen or alkyl, the ring A is a benzene ring having 1 to 4 the same or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent, and R3 is a group of the formula (2) wherein R8 is hydroxyalkoxyalkyl, methyl or ethyl and b is 1, or a pharmaceutically acceptable salt thereof or a hydrate thereof.
(13) The condensed thiophene compound of (11) above, wherein Raxe2x80x2 is alkyl, Rbxe2x80x2 is hydrogen or alkyl the ring A is a benzene ring having one substituent thereon selected from the group consisting of alkyl, alkoxy and halogen, or a benzene ring without a substituent, and R3 is a group of the formula (2) wherein R8 is methyl and b is 1, or a pharmaceutically acceptable salt thereof or a hydrate thereof.
(14) The condensed thiophene compound of (11) above, which is a member selected from the group consisting of
2-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine,
2-ethyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine,
2,8-dimethyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine, 
8-methoxy-2-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine,
2,6-dimethyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine,
2,9-dimethyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine,
2,3-dimethyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine,
8-chloro-2-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine and
8-fluoro-2-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine
or a pharmaceutically acceptable salt thereof or a hydrate thereof.
(15) A pharmaceutical agent comprising a condensed thiophene compound of formula (IB) or a pharmaceutically acceptable salt thereof or a hydrate thereof, a pharmaceutical composition comprising said compound and a pharmaceutically acceptable additive, and an antipsychotic agent comprising, as an active ingredient, a compound of formula (IB).
(16) A thienobenzoxazepinone compound of the formula (IIB) 
wherein Raxe2x80x2 and Rbxe2x80x2 are the same or different and each is hydrogen, alkyl, cycloalkyl, acyl, alkenyl, aryl, heteroaryl, aralkyl, alkoxy, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, acyloxyalkyl, acylaminoalkyl, halogen, alkyl halide or nitro, and ring A is a benzene ring having 1 to 4 the same or different substituents thereon selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, halogen, alkyl halide, nitro, amino, monoalkylamino, dialkylamino, acylamino, hydroxyl and cyano or a benzene ring without a substituent, which is an important intermediate for the synthesis of the of compound of the formula (IB).
(17) The thienobenzoxazepinone compound of (16) above, wherein Raxe2x80x2 and Rbxe2x80x2 are the same or different and each is hydrogen or alkyl, and the ring A is a benzene ring having 1 to 4 the same or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen, hydroxyl and alkyl halide, or a benzene ring without a substituent.
(18) The thienobenzoxazepinone compound of (16) above, which is a member selected from the group consisting of
2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one,
2,3-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one,
2,8-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one,
8-chloro-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one,
8-fluoro-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one,
8-methoxy-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one,
2,6-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one,
2,9-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one and
2-ethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one
In the present invention, each symbol used specifically means the following.
Alkyl is alkyl having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl.
Cycloalkyl is cycloalkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl and the like.
Alkoxy is alkoxy having 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.
Aryl is phenyl or naphthyl, with preference given to phenyl.
Heteroaryl is pyridyl, furyl, thienyl and the like.
Aralkyl is that wherein aryl has been substituted by alkyl having 1 to 5 carbon atoms and is exemplified by benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl and the like.
Hydroxyalkyl is hydroxyalkyl having 1 to 5 carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl, 4-hydroxybutyl, 1-hydroxy-1-methylethyl and the like.
Hydroxyalkoxyalkyl is that wherein alkyl having 1 to 4 carbon atoms has been bonded to hydroxyalkyl having 1 to 4 carbon atoms via one oxygen atom, and is exemplified by 2-(2-hydroxyethoxy)ethyl and the like.
Aminoalkyl is that wherein alkyl having 1 to 5 carbon atoms has been substituted by amino, which is exemplified by aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 1-aminopropyl, 4-aminobutyl, 1-amino-1-methylethyl and the like.
Monoalkylaminoalkyl is that wherein nitrogen atom of aminoalkyl is substituted by one alkyl having 1 to 5 carbon atoms, which is exemplified by methylaminomethyl, N-methyl-2-aminoethyl, N-methyl-1-aminoethyl, N-methyl-3-aminopropyl, N-methyl-1-aminopropyl, N-methyl-4-aminobutyl, N-methyl-1-amino-1-methylethyl and the like.
Dialkylaminoalkyl is that wherein nitrogen atom of aminoalkyl has been substituted by two alkyl having 1 to 5 carbon atoms, which is exemplified by dimethylaminomethyl, N,N-dimethyl-2-aminoethyl, N,N-dimethyl-1-aminoethyl, N,N-dimethyl-3-aminopropyl, N,N-dimethyl-1-aminopropyl, N,N-dimethyl-4-aminobutyl, N,N-dimethyl-1-amino-1-methylethyl and the like.
Alkoxyalkyl is that wherein alkyl having 1 to 5 carbon atoms has been substituted by alkoxy, such as methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl and the like.
Halogen is fluorine, chlorine, bromine or iodine.
Alkyl halide is that having 1 to 5 carbon atoms, such as fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl and the like.
Monoalkylamino is amino substituted by one alkyl having 1 to 5 carbon atoms, such as methylamino, ethylamino and the like.
Dialkylamino is amino substituted by two alkyl having 1 to 5 carbon atoms, such as dimethylamino, diethylamino and the like.
Acyl is that having 2 to 7 carbon atoms, such as acetyl, propanoyl, butanoyl, pivaloyl, benzoyl and the like.
Acylamino is that wherein amino or monoalkylamino is bonded to acyl having 1 to 5 carbon atoms, such as acetylamino, N-acetyl-N-methylamino and the like. As used herein, acyl means that having 2 to 5 carbon atoms, such as acetyl, propanoyl, butanoyl, pivaloyl and the like.
Alkoxycarbonyl is that having 2 to 8 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, pentoxycarbonyl and the like.
The ring B is preferably a benzene ring wherein the bond shown by a dotted line and a solid line is a double bond.
The group of the formula (1) as defined by the above-mentioned R5, R6, R7 and integer a is N-(Nxe2x80x2,Nxe2x80x2-dimethyl-2-aminoethyl)amino, N-(Nxe2x80x2,Nxe2x80x2-dimethyl-2-aminoethyl)-N-methylamino and the like.
The group of the formula (2) as defined by the above-mentioned R8 and integer b is piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-propylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl, 4-methylhomopiperazin-1-yl and the like, with preference given to 4-methylpiperazin-1-yl.
The group of the formula (3) as defined by the above-mentioned R9 is 8-methyl-3,8-diazabicyclo[3,2,1]octan-3-yl and the like.
The group of the formula (26) as defined by the above-mentioned R5 and R6 is amino, N,N-dimethylamino and the like.
The group of the formula (27) as defined by the above-mentioned R5, R6, R7 and integer a is N-(Nxe2x80x2,Nxe2x80x2-dimethyl-2-aminoethyl)amino-Nxe2x80x2-oxide, N-(Nxe2x80x2,Nxe2x80x2-dimethyl-2-aminoethyl)-N-methylamino-Nxe2x80x2-oxide and the like.
The group of the formula (28) as defined by the above-mentioned R8 and integer b is 4-methylpiperazine-4-oxide-1-yl and the like.
The group of the formula (29) as defined by the above-mentioned R9 is 8-methyl-3,8-diazabicyclo[3,2,1]octane-8-oxide-3-yl and the like.
The group of the formula (30) as defined by the above-mentioned R5 and R6 is amino-N-oxide, N,N-dimethylamino-N-oxide and the like.
The compound of the formula (I) is specifically a compound of the formula (IA) or a compound of the formula (IB).
The compound of the formula (IA), a pharmaceutically acceptable salt thereof and hydrates thereof are preferably a condensed thiophene compound of the formula (IA) wherein
X is NH, O or S,
R1 and R2 are the same or different and each is hydrogen, halogen, alkoxy or alkyl,
ring A is a benzene ring having 1 to 4 the same or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent,
ring B is a benzene ring wherein the bond shown by a dotted line and a solid line is a double bond, and
R3 is a group of the formula (2) wherein R8 is hydroxyalkoxyalkyl, methyl or ethyl and b is 1, a pharmaceutically acceptable salt thereof and hydrates thereof.
More preferred are a condensed thiophene compound of the formula (IA) wherein
X is NH,
R1 and R2 are the same or different and each is hydrogen, halogen, alkoxy or alkyl,
ring A is a benzene ring having 1 to 4 the same or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent,
ring B is a benzene ring wherein the bond shown by a dotted line and a solid line is a double bond, and
R3 is a group of the formula (2) wherein R8 is methyl or ethyl and b is 1, a pharmaceutically acceptable salt thereof and hydrates thereof.
Preferable compounds of the formula (IA) include the following compounds wherein the number denotes Example numbers.
(1) 12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(2) 8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(6) 8-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(7) 8-chloro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(8) 8-bromo-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(49) 9-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(10) 9-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(11) 9-chloro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(12) 9-bromo-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(13) 9-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1.5]benzodiazepine,
(50) 8,9-difluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(15) 8,10-difluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(16) 3-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(17) 8-fluoro-3-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(18) 2-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(19) 8-fluoro-2-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(20) 3-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(21) 8-fluoro-3-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(22) 8,9-dichloro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(23) 7,8-dichloro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(25) 3-bromo-8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(42) 3-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(43) 3-chloro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(45) 1-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(46) 4-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(47) 3,8-difluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine,
(48) 3-fluoro-8-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine, and
(51) 12-(4-ethylpiperazin-1-yl)-8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.
The present invention also encompasses pharmaceutically acceptable salts of the above-mentioned compounds and hydrates thereof.
The compound of the formula (IIA) is preferably a benzothiophene compound wherein
X is NH, O or S,
R1 and R2 are the same or different and each is hydrogen, halogen, alkoxy or alkyl,
ring A is a benzene ring having 1 to 4 the same or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent, and
ring B is a benzene ring wherein the bond shown by a dotted line and a solid line is a double bond or a cyclohexane ring wherein said bond is a single bond, provided that when X is NH, the bond shown by a dotted line and a solid line is not a single bond.
Specific compounds of the formula (IIA) include the following:
6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
8-chloro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
8-bromo-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
8-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
9-fluoro-6H-[1]benzothieno [2,3-b][1,5benzodiazepin-12(11H)-one,
9-chloro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
9-bromo-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
9-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
9-methoxy-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
8,9-difluoro-6H-[1]benzothieno2,3-b][1,5benzodiazepin-12(11 H)-one,
3-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
8-fluoro-3-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11 H)-one,
3-methoxy-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
8-fluoro-3-methoxy-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
2-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
8-fluoro-2-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
3,9-dimethyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one,
1,2,3,4-tetrahydro-8-methyl-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one,
8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b] 1,5]benzoxazepin-12(11H)-one,
[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one,
8-methyl-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one,
8-fluoro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one,
1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one,
1,2,3,4-tetrahydro-8-methyl-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one,
8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one,
[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one,
8-methyl-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one,
8-fluoro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one,
8,9-dichloro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
7,8-dichloro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
9-trifluoromethyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one, 3-bromo-8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
6-methyl-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
3-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
3-chloro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
1-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
4-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one,
3,8-difluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one and
3-fluoro-8-methyl-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12(11H)-one.
The compound of the formula (IB) is preferably a condensed thiophene compound wherein
Raxe2x80x2 and Rbxe2x80x2 are the same or different and each is hydrogen or alkyl,
ring A is a benzene ring having 1 to 4 the same or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen and alkyl halide, or a benzene ring without a substituent, and
R3 is a group of the formula (2) wherein R8 is hydroxyalkoxyalkyl, methyl or ethyl and b is 1, a pharmaceutically acceptable salt thereof and hydrates thereof.
More preferred are a condensed thiophene compound of the formula (IB) wherein
Raxe2x80x2 is alkyl,
Rbxe2x80x2 is hydrogen or alkyl,
ring A is a benzene ring having one substituent thereon selected from the group consisting of alkyl, alkoxy and halogen, or a benzene ring without a substituent, and
R3 is a group of the formula (2) wherein R8 is methyl and b is 1, a pharmaceutically acceptable salt thereof and hydrates thereof.
Preferable compounds of the formula (IB) include the following compounds wherein the numbers in parentheses are Example numbers:
(125) 2-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine,
(130) 2-ethyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine,
(138) 2,8-dimethyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine,
(142) 8-methoxy-2-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine,
(143) 2,6-dimethyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine,
(145) 2,9-dimethyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine,
(144) 2,3-dimethyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine,
(146) 8-chloro-2-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine, and
(147) 8-fluoro-2-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine.
The present invention also encompasses pharmaceutically acceptable salts of the above-mentioned compounds and hydrates thereof
The compound of the formula (IIB) is preferably a thienobenzoxazepinone compound wherein
Raxe2x80x2 and Rbxe2x80x2 are the same or different and each is hydrogen or alkyl and
ring A is a benzene ring having 1 to 4 the same or different substituents thereon selected from the group consisting of alkyl, alkoxy, halogen, hydroxyl and alkyl halide, or a benzene ring without a substituent.
Preferable compounds of the formula (IIB) include the following compounds wherein the numbers in parentheses are Example numbers:
(98) 2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one,
(101) 2,3-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one,
(102) 2,8-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one,
(105) 8-chloro-2methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one,
(106) 8-fluoro-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one,
(107) 8-methoxy-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one,
(108) 2,6-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one,
(109) 2,9-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one, and
(116) 2-ethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one.
The pharmaceutically acceptable salt of the compound of the formula (I), particularly formula (IA) or formula (IB), includes salts with inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and salts with organic acid, such as acetic acid, propionic acid,succinic acid, glycolic acid, lactic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, ascorbic acid, maleic acid, citric acid, tartaric acid, fumaric acid and the like. The compound of the formula (I), particularly formula (IA) or formula (IB) and pharmaceutically acceptable salts thereof may exist in the form of hydrates or solvates, and their hydrates (1/2 hydrates, monohydrates, dihydrates, trihydrates and the like) and solvates are also encompassed in the present invention.
When the inventive compounds include asymmetric atom, they can be obtained in the form of racemic mixture or optically active compound. When the inventive compounds include at least two asymmetric atoms, they can be obtained in the form of respective diastereomers or mixtures thereof. The present invention also encompasses these mixtures and individual isomers. The present invention further encompasses stereoisomers.
The synthetic methods of the compounds of the present invention are as follows.
Method 1: Synthetic Method of Compound of Formula (IA)
A benzothiophene compound of the formula (IIA) 
wherein each symbol is as defined above is kept with a suitable chlorinating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride and the like, in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene, chloroform, 1,2-dichloroethane, an optionally mixed solvents therefrom and the like or without solvent, at room temperature to 170xc2x0 C. for 1 to 24 hr to give a compound of the formula (4A) 
wherein each symbol is as defined above. The obtained compound of the formula (4A) is kept with a compound of the formula (5)
H-R3xe2x80x83xe2x80x83(5)
wherein R3 is as defined above, in a solvent that does not adversely affect the reaction such as benzene, toluene, xylene, chloroform, 1,2-dichloroethane, an optionally mixed solvents therefrom and the like or without solvent, at room temperature to 170xc2x0 C. for 1 to 24 hr to give a compound of the formula (IA).
Method 2: Synthetic Method of Compound of Formula (IA)
A benzothiophene compound of the formula (IIA) is kept with a suitable sulfurating agent such as diphosphorus tetrasulfate, Lawesson reagent and the like in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene, chloroform, 1,2-dichloroethane, an optionally mixed solvents therefrom and the like, or without solvent at room temperature to 170xc2x0 C. for 1 to 24 hr to give a compound of the formula (7) 
wherein each symbol is as defined above. The obtained compound of the formula (7) is reacted with a suitable methylating agent such as methyl iodide, methyl bromide and the like in a solvent that does not adversely affect the reaction such as tetrahydrofuran, N,N-dimethylformamide, acetonitrile, N-methylpyrolidone, dichloromethane, chloroform, 1,2-dichloroethane, an optionally mixed solvents therefrom and the like, in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine and the like or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyllithium and the like, or without a base to give a compound of the formula (8) 
wherein each symbol is as defined above. The obtained compound of the formula (7) or the formula (8) is kept with a compound of the formula (5) in a solvent that does not adversely affect the reaction, such as tetrahydrofuran, N,N-dimethylformamide, acetonitrile, N-methylpyrolidone, dichloromethane, benzene, toluene, xylene, chloroform, 1,2-dichloroethane, an optionally mixed solvents therefrom and the like, or without solvent, at room temperature to 170xc2x0 C. for 1 to 24 hr to give a compound of the formula (IA).
Method 3: Synthetic Method of Compound of Formula (IA) Wherein X is NH, N-R4, O or S
A benzothiophene compound of the formula (9) 
wherein R10 is alkyl, R11 is halogen and other symbols are as defined above, is kept with a compound of the formula (10) 
wherein R12 is NH2, NH-R4, OH or SH and ring A is as defined above, in a solvent that does not adversely affect the reaction, such as N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrolidone, tetrahydrofuran, ethanol, 1,4-dioxane, an optionally mixed solvent therefrom and the like, or without solvent, in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine and the like or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyllithium and the like at xe2x88x9220xc2x0 C. to 170xc2x0 C. for 1 to 24 hr to give a compound of the formula (11) 
wherein each symbol is as defined above.
A compound of the formula (11a) 
wherein R13 is hydrogen or alkyl and other symbols are as defined above, which is a compound of the formula (11) wherein X is NH or N-R4, can be also synthesized by the following method.
For example, a benzothiophene compound of the formula (12) 
wherein each symbol is as defined above, is kept with a compound of the formula (13) 
wherein R14 is halogen and ring A is as defined above, in a solvent that does not adversely affect the reaction, such as N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrolidone, tetrahydrofuran, ethanol, 1,4-dioxane, an optionally mixed solvents therefrom and the like, or without solvent, in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine and the like or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyllithium and the like at xe2x88x9220xc2x0 C. to 170xc2x0 C. for 1 to 24 hr to give the above-mentioned compound of the formula (11a).
In particular, of the compounds of the formula (11a), a compound wherein R13 is alkyl can be also obtained by keeping a compound wherein R13 is hydrogen with an alkyl halide of the formula (6) to be mentioned later, in a solvent that does not adversely affect the reaction, such as N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrolidone, tetrahydrofuran, 1,4-dioxane, an optionally mixed solvent therefrom and the like, or without solvent, in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine and the like, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyllithium, lithium diisopropylamine and the like at room temperature to 170xc2x0 C. for 1 to 24 hr.
The obtained compound of the formula (11) is kept with hydrogen at normal pressure to 100 atm, in a solvent that does not adversely affect the reaction such as ethanol, methanol, ethyl acetate, dimethylformamide, acetic acid, water, an optionally mixed solvent therefrom and the like, or without solvent, in the presence of a suitable metal catalyst such as palladium-carbon, palladium black, palladium hydroxide, Raney nickel, platinium oxide and the like at room temperature to 150xc2x0 C. for 1 to 24 hr to give a compound of the formula (14) 
wherein each symbol is as defined above.
The compound of the formula (14) can be also obtained by keeping a compound of the formula (11) with a suitable inorganic reagent such as iron, zinc, tin(II) chloride and the like, in a solvent that does not adversely affect the reaction, such as ethanol, methanol, 1,4-dioxane, dimethylformamide, acetic acid, water, an optionally mixed solvent therefrom and the like, in the presence of a suitable acid such as hydrochloric acid, acetic acid and the lik at xe2x88x9220xc2x0 C. to 150xc2x0 C. for 1 to 24 hr.
In addition, of the compounds of the formula (14), a compound wherein X is S or O can be also obtained by keeping a compound of the formula (9) with a compound of the formula (25) 
wherein R16 is OH or SH and ring A is as defined above, in a solvent that does not adversely affect the reaction, such as N,N-dimethyformamide, dimethyl sulfoxide, N-methylpyrolidone, tetrahydrofuran, ethanol, 1,4-dioxane, an optionally mixed solvent therefrom and the like, or without solvent, in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine and the like or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyllithium and the like at xe2x88x9220xc2x0 C. to 150xc2x0 C. for 1 to 24 hr.
The obtained compound of the formula (14) is kept with a compound of the formula (5) in a solvent that does not adversely affect the reaction, such as anisole, toluene, xylene, mesitylene, nitrobenzene, 1,2-dichloroethane, an optionally mixed solvent therefrom and the like, or without solvent, in the presence of a suitable Lewis acid such as titanium tetrachloride, thin tetrachloride, aluminium chloride and the like at room temperature to 170xc2x0 C. for 1 to 24 hr to give a compound of the formula (IA).
Method 4:
A compound of the formula (IAa) 
wherein each symbol is as defined above, which is a compound of the formula (IA) wherein X is N-R4, can be also obtained by keeping a benzothiophene compound of the formula (IAb) 
wherein each symbol is as defined above, with an alkyl halide of the formula (6)
Hal-R4xe2x80x83xe2x80x83(6)
wherein Hal is halogen and R4 is as defined above, in a solvent that does not adversely affect the reaction, such as N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrolidone, tetrahydrofuran, 1,4-dioxane, an optionally mixed solvent therefrom and the like, or without solvent, in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine and the like, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyllithium and the like at room temperature to 170xc2x0 C. for 1 to 24 hr.
Method 5: 
A compound of the formula (IAc)
wherein c is 1 or 2 and other symbols are as defined above, which is a compound of the formula (IA) wherein X is SO or SO2, can be also obtained by keeping a benzothiophene compound of the formula (IAd) wherein each symbol is as defined above, with an oxidizing agent such as hydrogen peroxide, m-chloroperbenzoic acid, sodium periodate, sodium perbromate and the like, in a solvent that does not adversely affect the reaction, such as water, ethanol, acetic acid, formic acid, dichloromethane, chloroform, an 
optionally mixed solvent therefrom and the like, or without solvent, at xe2x88x9278xc2x0 C. to 120xc2x0 C. for 1 to 24 hr.
Method 6: Synthetic Method of Compound of Formula (IIA)
A compound of the formula (14) is kept with an organic base, such as pyridine, triethylamine, diisopropylethylamine and the like, or an inorganic base, such as sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyllithium and the like, or a suitable Lewis acid, such as titanium tetrachloride, thin tetrachloride, aluminium chloride, boron trifluoride and the like, or a suitable acid, such as sulfuric acid, phosphoric acid and the like, in a solvent that does not adversely affect the reaction, such as dichloromethane, chloroform, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, benzene, toluene, xylene, an optionally mixed solvent therefrom and the like, at room temperature to 170xc2x0 C. for 1 to 24 hr to give a compound of the formula (IIA).
A compound of the formula (14) is kept with a suitable inorganic base, such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, in a solvent that does not adversely affect the reaction, such as methanol, ethanol, water, tetrahydrofuran, 1,4-dioxane, an optionally mixed solvent therefrom and the like, at room temperature to 150xc2x0 C. for 1 to 24 hr to give a compound of the formula (15) 
wherein each symbol is as defined above. The obtained compound of the formula (15) is kept with a suitable condensing agent, such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-Nxe2x80x2-3-dimethylaminopropylcarbodiimide, diethylphosphoryl azide, diphenylphosphoryl azide and the like, in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene, hexane, ethyl acetate, diethyl ether, tetrahydrofuran, dioxane, chloroform, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrolidone, pyridine, an optionally mixed solvent therefrom and the like, at room temperature to 100xc2x0 C. for 10 min to 24 hr to give a compound of the formula (IIA).
Method 7: Synthetic Method of Compound of Formula (IIA)
A compound of the formula (16) 
wherein each symbol is as defined above, is kept with a suitable chlorinating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride and the like in a solvent that does not adversely affect the reaction such as benzene, toluene, xylene, chloroform, 1,2-dichloroethane, an optionally mixed solvent therefrom and the like, or without solvent, at room temperature to 170xc2x0 C. for 1 to 24 hr to give a compound of the formula (17) 
wherein each symbol is as defined above. The obtained compound of the formula (17) is kept with a compound of the formula (18) 
wherein each symbol is as defined above, in a solvent that does not adversely affect the reaction such as benzene, toluene, xylene, hexane, ethyl acetate, diethyl ether, tetrahydrofuran, dioxane, chloroform, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrolidone, pyridine, an optionally mixed solvent therefrom and the like, or without solvent, in the presence of an organic base, such as pyridine, triethylamine, diisopropylethylamine and the like, or an inorganic base, such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like at room temperature to 170xc2x0 C. for 10 min to 24 hr to give a compound of the formula (19) 
wherein each symbol is as defined above.
A compound of the formula (19) can be also obtained by keeping a compound of the formula (16) with a compound of the formula (18) in a solvent that does not adversely affect the reaction such as benzene, toluene, xylene, hexane, ethyl acetate, diethyl ether, tetrahydrofuran, dioxane, chloroform, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrolidone, pyridine, an optionally mixed solvent therefrom and the like and a suitable condensing agent, such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-Nxe2x80x2-3-dimethylaminopropylcarbodiimide, diethylphosphoryl azide, diphenylphosphoryl azide and the like at room temperature to 100xc2x0 C. for 10 min to 24 hr.
The obtained compound of the formula (19) is kept in a solvent that does not adversely affect the reaction, such as methanol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrolidone, hexamethylphosphorous triamide, benzene, toluene, xylene, chloroform, dichloroethane and the like, an optionally mixed solvent therefrom and the like, in the presence of an organic base, such as pyridine, triethylamine, N,N-diisopropylethylamine and the like, or an inorganic base, such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like at room temperature to 170xc2x0 C. for 10 min to 24 hr to give a compound of the formula (IIA).
Method 8:
A compound of the formula (IIAa) 
wherein each symbol is as defined above, which is a compound of the formula (IIA) wherein X is SO or SO2, can be obtained by keeping a benzothiophene compound of the formula (IIAb) 
wherein each symbol is as defined above, with an oxidizing agent, such as hydrogen peroxide, m-chloroperbenzoic acid, sodium periodate, sodium perbromate and the like, in a solvent that does not adversely affect the reaction, such as water, ethanol, acetic acid, formic acid, dichloromethane, chloroform, an optionally mixed solvent therefrom and the like, or without solvent, at xe2x88x9278xc2x0 C. to 120xc2x0 C. for 1 to 24 hr.
Method 9:
A compound of the formula (IIAc) 
wherein each symbol is as defined above, which is a compound of formula (IIA) wherein X is N-R4, can be also obtained by, for example, keeping a benzothiophene compound of the formula (IIAd) 
wherein each symbol is as defined above, with an alkyl halide of the formula (6), in a solvent that does not adversely affect the reaction, such as N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrolidone, tetrahydrofuran, 1,4-dioxane, an optionally mixed solvent therefrom and the like, or without solvent, in the presence of an organic base, such as pyridine, triethylamine, diisopropylethylamine and the like, or an inorganic base, such as sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyllithium, lithium diisopropylamide and the like at room temperature to 170xc2x0 C. for 1 to 24 hr.
Method 10:
A compound of the formula (IIAe) 
wherein each symbol is as defined above provided that a compound wherein X is NH is excluded, which is a compound of formula (IIA) wherein ring B is a benzene ring, can be also obtained by keeping a 1,2,3,4-tetrahydrobenzothiophene compound of the formula (IIAf) 
wherein each symbol is as defined above, with a suitable oxidizing agent, such as sulfur, N-bromosuccinimide, N-chrolosuccinimide, N-iodosuccinimide, dichlorodicyano-p-benzoquinone, or a suitable noble metallic catalyst, such as palladium-carbon, palladium hydroxide, palladium black, platinium oxide and the like, in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene, mesitylene, chloroform, carbon tetrachloride, 1,4-dioxane, an optionally mixed solvent therefrom and the like, or without solvent at 0xc2x0 C. to 250xc2x0 C. for 1 to 48 hr. 
wherein each symbol is as defined above, which is a compound of formula (IIA) wherein substituent on ring A is amino, can be obtained by keeping a compound of the formula (IIAh) 
wherein each symbol is as defined above, which is a compound of formula (IIA) wherein a substituent on ring A is nitro, with hydrogen, in a solvent that does not adversely affect the reaction, such as methanol, ethanol, ethyl acetate, dioxane, benzene, toluene, xylene, diethyl ether, chloroform, 1,2-dichloroethane, an optionally mixed solvent therefrom and the like, using palladium-carbon, palladium hydroxide, platinium oxide and the like as a catalyst at 0xc2x0C. to 100xc2x0 C. and from normal pressure to 100 atm for 10 min to 24 hr.
Method 12:
A compound of the formula (IIAi) 
wherein R15 is fluorine, chlorine, bromine, iodine or cyano and other symbols are as defined above, which is a compound of formula (IIA) wherein substituent on ring A is cyano or halogen, can be obtained by diazotizing a compound of the formula (IIAg) in a solvent that does not adversely affect the reaction, such as water, diluted hydrochloric acid and the like and using sodium nitrite and the like at xe2x88x9210xc2x0 C. to room temperature and keeping with fluoroboric acid, hydrogen fluoride-pyridine, sodium chloride, cuprous chloride, sodium bromide, cuprous bromide, sodium iodide, potassium iodide and the like at xe2x88x9210xc2x0 C. to 100xc2x0 C.
Method 13: Synthetic Method of Compound of Formula (IA) Wherein X is NH and Bond Shown by Dotted Line and Solid Line in B Ring is Double Bond
Using a benzylcyanide compound of the formula (20) 
wherein each symbol is as defined above, as a starting material and according to the method described in Japanese Patent Unexamined Publication No. 7-89965 to give a benzothiophene compound of the formula (21) 
wherein each symbol is as defined above.
The obtained compound of the formula (21) is kept with a compound of the formula (13) in a solvent that does not adversely affect the reaction, such as N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrolidone, tetrahydrofuran, ethanol, 1,4-dioxane, an optionally mixed solvent therefrom and the like, or without solvent, in the presence of an organic base, such as pyridine, triethylamine, diisopropylethylamine and the like, or inorganic base, such as sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium alkoxide, butyllithium or the like at xe2x88x9250xc2x0 C. to 170xc2x0 C. for 1 to 24 hr to give a compound of the formula (22) 
wherein each symbol is as defined above.
The obtained compound of the formula (22) is kept with a suitable reducing agent such as iron, zinc, tin(II) chloride and the like, in a solvent that does not adversely affect the reaction, such as ethanol, methanol, 1,4-dioxane, dimethylformamide, acetic acid, water, an optionally mixed solvent therefrom and the like, in the presence of a suitable acid, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid and the like at xe2x88x9220xc2x0 C. to 150xc2x0 C. for 1 to 24 15 hr to give a compound of the formula (23) 
wherein each symbol is as defined above or a salt thereof with an inorganic acid, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like.
A compound of the formula (23) can be obtained by keeping a compound of the formula (22) with hydrogen from normal pressure to 100 atm in a solvent that does not adversely affect the reaction, such as ethanol, methanol, ethyl acetate, dimethylformamide, acetic acid, water, an optionally mixed solvent therefrom and the like or without solvent, in the presence of a suitable metallic catalyst, such as palladium-carbon, palladium black, palladium hydroxide, Raney nickel, platinium oxide and the like at room temperature to 150xc2x0 C. for 1 to 24 hr, or by keeping a compound of the formula (24) 
wherein each symbol is as defined above, which is obtained by keeping with a suitable reducing agent, such as sodium hydrosulfite, iron, zinc, tin(II) chloride and the like in the presence of hydrochloric acid, acetic acid and the like, or under neutral conditions, at xe2x88x9220xc2x0 C. to 150xc2x0 C. for 1 to 24 hr is kept in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, ethanol, methanol, acetic acid, water, an optionally mixed solvent therefrom and the like, in the presence or absence of an suitable inorganic acid, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like, at room temperature to 180xc2x0 C. for 1 to 24 hr.
The obtained compound of the formula (23) is kept with a compound of the formula (1), (2), (3), (26), (27), (28), (29) or (30) in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene, dimethyl sulfoxide, N,N-dimethylformamide, an optionally mixed solvent therefrom and the like, or without solvent, in the presence of a suitable organic base, such as pyridine, triethylamine, diisopropylethylamine and the like, or inorganic base, such as potassium carbonate, sodium carbonate and the like, or in the absence of a base at room temperature to 180xc2x0 C. for 1 to 20 hr to give a compound of the formula (IA) wherein X is NH and the bond shown by a dotted line and a solid line in the B ring is a double bond.
Method 14Compounds of Formulas (IAe) and (IAf) 
wherein each symbol is as defined above, provided that when X is NH, the bond shown by a dotted line and a solid line is not a single bond, which are the compounds of the formula (IA) wherein R3 is of formula (2) or (3) and R8 or R9 is hydrogen, can be also obtained by keeping a compound wherein R3 is alkoxycarbonyl or acyl of the formula (2a), (2b), (3a) or (3b) 
wherein R17 is alkyl or aralkyl, R18 is alkyl or aryl and b is as defined above, in a solvent that does not adversely affect the reaction, such as ethanol, methanol, 1,4-dioxane, tetrahydrofuran, benzene, toluene, water, an optionally mixed solvent therefrom and the like or without using a solvent, in the presence of an inorganic acid such as hydrochloric acid, sulfuric acid and the like or an organic acid such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and the like at 0xc2x0 C. to 150xc2x0 C. for 1 to 18 hr.
The compounds (IAe) and (IAf) can be also obtained by keeping compounds of the formulas (2c) and (3c) 
wherein R22 is aryl and b is as defined above, with hydrogen at normal pressure to 100 atm in a solvent that does not adversely affect the reaction, such as ethanol, methanol, ethyl acetate, dimethylformamide, acetic acid, water, an optionally mixed solvent therefrom and the like, or without solvent, in the presence of a suitable metallic catalyst, such as palladium-carbon, palladium black, palladium hydroxide, Raney nickel, platinium oxide and the like at room temperature to 150xc2x0 C. for 1 to 24 hr.
Method 15: Compounds of Formulas (IAg) and (IAh) 
wherein R8xe2x80x2 and R9xe2x80x2 are each acyl or alkoxycarbonyl and other symbols are as defined above, provided that when X is NH and the bond shown by a dotted line and a solid line is not a single bond, which are the compounds of the formula (IA) wherein R3 is formula (2) or (3) and R8 or R9 is acyl or alkoxycarbonyl, can be obtained by keeping compounds (IAe) and (IAf) (R8 or R9 is hydrogen) with a suitable acylating agent, such as acyl halide of the formula (31)
Hal-CO-R19xe2x80x83xe2x80x83(31)
wherein Hal is halogen and R19 is alkyl or aryl, or acid anhydride of the formula (32)
(R19CO)2O xe2x80x83xe2x80x83(32)
wherein R19 is as defined above, or ester halide of the formula (33)
xe2x80x83Hal-COOR20 xe2x80x83xe2x80x83(33)
wherein Hal is halogen and R20 is alkyl or aralkyl as an alkoxycarbonylating agent, in a solvent that does not adversely affect the reaction such as benzene, toluene, xylene, chloroform, 1,4-dioxane, tetrahydrofuran, an optionally mixed solvent therefrom and the like, or without solvent, in the presence of a basic reagent, such as pyridine, triethylamine, N, N-dimethylaminopyridine, sodium hydride, potassium carbonate, sodium hydroxide, potassium tert-butoxide, sodium alkoxide, butyllithium, lithium diisopropylamine and the like, at xe2x88x9250 to 150xc2x0 C. for 10 min to 15 hr.
Method 16: Compounds of Formulas (IAi) and (IAj) 
wherein R8xe2x80x3 and R9xe2x80x3 are each alkyl, cycloalkyl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl and other symbols are as defined above, provided that when X is NH, the bond shown by a dotted line and a solid line is not a single bond, which are the compounds of the formula (IA) wherein R3 is of formula (2) or (3) and R8 or R9 is alkyl, cycloalkyl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl, can be obtained by keeping compounds (IAe) and (IAf) (R8 or R9 is hydrogen) with a suitable alkylating agent, such as compound of the formula (34)
Hal-R21 xe2x80x83xe2x80x83(34)
wherein Hal is halogen and R21 is alkyl, cycloalkyl, aralkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene, chloroform, 1,4-dioxane, tetrahydrofuran, an optionally mixed solvent therefrom and the like, or without solvent, in the presence of a suitable basic reagent such as pyridine, triethylamine, N,N-dimethylaminopyridine, sodium hydride, potassium carbonate, sodium hydroxide, potassium tert-butoxide, sodium alkoxide, butyllithium, lithium diisopropylamine and the like at xe2x88x9250 to 200xc2x0 C. for 10 min to 24 hr.
Method 17:
Of the compounds of the formula (IA), a compound wherein R3 is of the formula (27), (28), (29) or (30) can be obtained by keeping the corresponding compound (1), (2), (3) or (26) with a suitable oxidizing agent, such as aqueous hydrogen peroxide, m-chloroperbenzoic acid, tert-butyl hydroperoxide and the like in a solvent that does not adversely affect the reaction such as methylene chloride, chloroform, 1,2-dimethoxyethane, benzene, toluene, diethyl ether, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, water, an optionally mixed solvent therefrom and the like at xe2x88x9230 to 130xc2x0 C. for 10 min to 12 hr.
Method 18:
A compound of the formula (IIA) wherein X is O, S, SO or SO2 and the bond shown by a dotted line and a solid line in the B ring is a double bond can be also obtained by keeping a compound of the formula (IIA) wherein X is O, S, SO or SO2 and the bond shown by a dotted line and a solid line in the B ring is a single bond in a solvent that does not adversely affect the reaction, such as benzene, toluene, xylene, mesitylene, dichloromethane, chloroform, ethyl acetate, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, an optionally mixed solvent therefrom and the like, in the presence of a suitable oxidizing agent, such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, chloranil, manganese dioxide, nickel peroxide, palladium-carbon, lead tetraacetate and the like at room temperature to 200xc2x0 C. for 1 to 24 hr.
Method 19: Synthetic Method of Compound of Formula (IB)
A thienobenzoxazepinone compound of the formula (IIB) 
wherein each symbol is as defined above, is kept with a suitable chlorinating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride and the like in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., benzene, toluene, xylene, chloroform, 1,2-dichloroethane, an optionally mixed solvent therefrom and the like), or without solvent, at room temperature to 170xc2x0 C. for 1 to 24 hr to give a compound of the formula (4B) 
wherein each symbol is as defined above. Then, a compound of the formula (4B) is kept with a compound of the formula (5)
H-R3 xe2x80x83xe2x80x83(5)
wherein R3 is as defined above, in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., benzene, toluene, xylene, chloroform, 1,2-dichloroethane, an optionally mixed solvent therefrom and the like), or without solvent, at room temperature to 170xc2x0 C. for 1 to 24 hr to give a compound of the formula (IB).
Method 20: Synthetic Method of Compound of Formula (IBa) 
wherein W is an oxygen atom or nitrogen atom bonded with hydrogen or one C1-C5 alkyl, R23 and R24 are the same or different and each is hydrogen, C1-C4 alkyl and the like, c is an integer of 0 to 4, and other symbols are as defined above, which is a compound of formula (IB) (Raxe2x80x2 is hydroxyalkyl, aminoalkyl or monoalkylaminoalkyl)
For example, a compound of the formula (IBb) (Raxe2x80x2 is acyloxyalkyl or acylaminoalkyl), which is synthesized according to Method 19 
wherein R25 is hydrogen or alkyl having 1 to 4 carbon atoms, and the like and other symbols are as defined above, is kept with a base such as sodium hydroxide, potassium hydroxide, ammonia and the like or an acid such as hydrochloric acid, hydrobromic acid, acetic acid, formic acid, sulfuric acid and the like, in water or in a mixed solvent of water and a suitable solvent, such as methanol, ethanol, pyridine, dioxane and the like at room temperature to 100xc2x0 C. for 10 min to 24 hr to give a compound of the formula (IBa).
Method 21: Synthetic Method of Compound of Formula (IBc) 
wherein each symbol is as defined above, which is a compound of the formula (IB) wherein substituent on ring A is hydroxy, amino or monoalkyamino
For example, a compound of the formula (IBd) which is a compound of the formula (IB) wherein substituent on ring A is acyloxy or acylamino 
wherein each symbol is as defined above, is kept with a base such as sodium hydroxide, potassium hydroxide, ammonia and the like or an acid such as hydrochloric acid, hydrobromic acid, acetic acid, formic acid, sulfuric acid and the like in water or a mixed solvent of water and a suitable solvent, such as methanol, ethanol, pyridine, dioxane and the like, at room temperature to 100xc2x0 C. for 10 min to 24 hr to give a compound of the formula (IBc).
Method 22: Synthetic Method of Compound of Formula (IBe) 
wherein each symbol is as defined above, which is the compound of formula (IB) wherein substituent on ring A is amino
A compound of the formula (IBf) 
wherein each symbol is as defined above, which is the compound of the formula (IB) wherein substituent on ring A is nitro, and which is synthesized according to Method 19, is kept with hydrogen in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., methanol, ethanol, ethyl acetate, dioxane, benzene, toluene, xylene, diethyl ether, chloroform, 1,2-dichloroethane, an optionally mixed solvent therefrom and the like), using palladium-activated carbon, palladium hydroxide, platinium oxide and the like as a catalyst, at 0xc2x0 C. to 100xc2x0 C. at normal pressure to 100 atm for 10 min to 24 hr, to give a compound of the formula (IBe).
Method 23: Synthetic Method of Compound of Formula (IIB)
2-Halogeno-3-thiophenecarboxylic acid derivative of the formula (35) 
wherein Hal is halogen and other symbols are as defined above, is kept with a suitable chlorinating agent, such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride and the like in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., benzene, toluene, xylene, chloroform, 1,2-dichloroethane, an optionally mixed solvent therefrom and the like), or without solvent, at room temperature to 170xc2x0 C. for 1 to 24 hr to give a compound of the formula (36) 
wherein each symbol is as defined above.
The obtained compound of the formula (36) is kept with a compound of the formula (37) 
wherein ring A is as defined above, in a suitable solvent such as a solvent that does not adversely affect the reaction (e.g., benzene, toluene, xylene, hexane, ethyl acetate, diethyl ether, tetrahydrofuran, dioxane, chloroform, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrolidone, pyridine, an optionally mixed solvent therefrom and the like), or without solvent, in the presence of an organic base, such as pyridine, triethylamine, diisopropylethylamine and the like, or an inorganic base, such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like, at room temperature to 170xc2x0 C. for 10 min to 24 hr to give a compound of the formula (38) 
wherein each symbol is as defined above.
The compound of the formula (38) can be also obtained by keeping a compound of the formula (35) and a compound of the formula (37) in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., benzene, toluene, xylene, hexane, ethyl acetate, diethyl ether, tetrahydrofuran, dioxane, chloroform, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrolidone, pyridine, an optionally mixed solvent therefrom and the like), together with a suitable condensing agent, such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-Nxe2x80x2-3-dimethylaminopropylcarbodiimide, diethylphosphoryl azide, diphenylphosphoryl azide and the like at room temperature to 100xc2x0 C. for 10 min to 24 hr.
The obtained compound of the formula (38) is kept in suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., methanol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrolidone, hexamethylphosphorus triamide, benzene, toluene, xylene, chloroform, dichloroethane and the like, an optionally mixed solvent therefrom and the like), in the presence of an organic base, such as pyridine, triethylamine, N,N-diisopropylethylamine and the like, or an inorganic base, such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like or metal alkoxide or sodium ethoxide, sodium methoxide, potassium tert-butoxide and the like at room temperature to 170xc2x0 C. for 10 min to 24 hr to give a compound of the formula (IIB).
Method 24: Synthetic Method of Compound of Formula (IIBa) 
wherein R26 is alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, butyl and the like and other symbols are as defined above, which is a compound of formula (IIB) wherein Raxe2x80x2 is acyl other than formyl
A compound of the formula (IIBb) which is a compound of the formula (IIB) wherein Raxe2x80x2 is hydrogen and synthesized according to Method 23 
wherein each symbol is as defined above, is kept with a compound of the formula (39) 
wherein each symbol is as defined above or a compound of the formula (40) 
wherein R26 is as defined above, in the presence of an aluminium chloride and the like in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., nitrobenzene, hexane, chloroform, 1,2-dichloroethane and the like, an optionally mixed solvent therefrom and the like), from 0xc2x0 C. to 100xc2x0 C. for 10 min to 24 hr to give a compound of the formula (IIBa).
Method 25: Synthetic Method of Compound of Formula (IIBc) 
wherein each symbol is as defined above, which is a compound of formula (IIB) wherein Raxe2x80x2 is formyl
A compound of the formula (IIBc) can be obtained by keeping a compound of the formula (IIBb) with aluminium chloride and the like in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., nitrobenzene, hexane, chloroform, 1,2-dichloroethane and the like, an optionally mixed solvent therefrom and the like), in the presence of dichloromethylmethyl ether and the like at 0xc2x0 C. to 100xc2x0 C. for 10 min to 24 hr.
In addition, a compound of the formula (IIBc) can be also obtained by keeping a compound of the formula (IIBb) with N,N-dimethylformamide, N-methylformanilide, N-methylmorpholine, N,N-diisopropylformamide and the like, in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrolidone, hexamethylphosphorous triamide, benzene, toluene, xylene, chloroform, dichloroethane and the like, an optionally mixed solvent therefrom and the like), or without solvent, in the presence of an halogenating agent such as phosphorus oxychloride, phosgene, oxalyl chloride, thionyl chloride and the like, at 0xc2x0 C. to 100xc2x0 C. for 10 min to 24 hr.
Method 26: Synthetic Method of Compound of Formula (IIBd) 
wherein each symbol is as defined above, which is a compound of formula (IIB) wherein Raxe2x80x2 is hydroxyalkyl, aminoalkyl or monoalkylaminoalkyl
A compound of the formula (IIBe) (IIB wherein Raxe2x80x2 is acyloxyalkyl or acylaminoalkyl) 
wherein each symbol is as defined above, synthesized according to the Method 36 to be mentioned later is kept with a base such as sodium hydroxide, potassium hydroxide, ammonia and the like or an acid such as hydrochloric acid, hydrobromic acid, acetic acid, formic acid, sulfuric acid and the like in a suitable solvent such as water and a mixed solvent of water and a suitable solvent (e.g., methanol, ethanol, pyridine, dioxane and the like), at room temperature to 100xc2x0 C. for 10 min to 24 hr to give a compound of the formula (IIBd).
Method 27: Synthetic Method of Compound of Formula (IIBf): 
wherein R27 and R28 are the same or different and each is alkyl having 1 to 4 carbon atoms and other symbols are as defined above, from among the compounds of formula (IIB) wherein Raxe2x80x2 is hydroxyalkyl
For example, a compound of the formula (IIB g) 
wherein each symbol is as defined above, is kept with an alkyl metal compound such as a compound of the formula (41)
R28MgBr xe2x80x83xe2x80x83(41)
wherein R28 is alkyl having 1 to 4 carbon atoms, and the like, in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., benzene, toluene, xylene, diethyl ether, tetrahydrofuran, chloroform, dichloroethane, an optionally mixed solvent therefrom and the like), at 0xc2x0 C. to 100xc2x0 C. for 10 min to 24 hr to give a compound of the formula (IIBf).
Method 28: Synthetic Method of Compound of Formula (IIBh) 
wherein each symbol is as defined above, from among the compounds of formula (IIB) wherein Raxe2x80x2 is hydroxyalkyl
For example, a compound of the formula (IIBi) 
wherein each symbol is as defined above is kept with sodium boron hydride, lithium aluminium hydride and the like in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., methanol, ethanol, benzene, toluene, xylene, diethyl ether, tetrahydrofuran, chloroform, dichloroethane, an optionally mixed solvent therefrom and the like), at 0xc2x0 C. to 100xc2x0 C. for 10 min to 24 hr to give a compound of the formula (IIBh).
Method 29: Synthetic Method of Compound of Formula (IIBj) 
wherein each symbol is as defined above, from among the compounds of formula (IIB) wherein Raxe2x80x2 is hydroxyalkyl
For example, a compound of the formula (IIBc) is kept with a compound of the formula (41) in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., benzene, toluene, xylene, diethyl ether, tetrahydrofuran, chloroform, dichloroethane, an optionally mixed solvent therefrom and the like), at 0xc2x0 C. to 100xc2x0 C. for 10 min to 24 hr to give a compound of the formula (IIBj).
Method 30: Synthetic Method of Compound of Formula (IIBk) 
wherein R29, R30 and R31 are the same or different and each is hydrogen or alkyl having 1 to 3 carbon atoms and other symbols are as defined above, from among the compounds of formula (IIB) wherein Raxe2x80x2 is alkenyl
Of the compounds of formula (IIB) wherein Raxe2x80x2 is hydroxyalkyl, a compound of the formula (IIBl) 
wherein each symbol is as defined above, is kept in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., methanol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrolidone, hexamethylphosphorous triamide, benzene, toluene, xylene, chloroform, dichloroethane and the like, an optionally mixed solvent therefrom and the like) in the presence of an acid, such as hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid and the like at room temperature to 190xc2x0 C. to give a compound of the formula (IIBk).
Method 31: Synthetic Method of Compound of Formula (IIBm) 
wherein each symbol is as defined above, from among the compounds of formula (IIB) wherein Raxe2x80x2 is alkyl
A compound of the formula (IIBi) is kept with triethylsilane, lithium aluminium hydride and the like in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., trifluoroacetic acid, benzene, toluene, xylene, diethyl ether, chloroform, dichloroethane, an optionally mixed solvent therefrom and the like) at 0xc2x0 C. to 100xc2x0 C. for 10 min to 24 hr to give a compound of the formula (IIBm).
Method 32: Synthetic Method of Compound of Formula (IIBn) 
wherein R32 is alkyl having 2 to 5 carbon atoms and other symbols are as defined above, which is a compound of formula (IIB) wherein Raxe2x80x2 is alkyl other than methyl
A compound of the formula (IIBo) 
wherein R33 is alkenyl having 2 to 5 carbon atoms and other symbols are as defined above, which is a compound of the formula (IIB) wherein Raxe2x80x2 is alkenyl, is kept with hydrogen in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., methanol, ethanol, ethyl acetate, dioxane, benzene, toluene, xylene, diethyl ether, chloroform, 1,2-dichloroethane, an optionally mixed solvent therefrom and the like) using palladium-activated carbon, palladium hydroxide, platinium oxide and the like as a catalyst, at 0xc2x0 C. to 100xc2x0 C. from normal pressure to 100 atm for 10 min to 24 hr to give a compound of the formula (IIBn).
Method 33: Synthetic Method of Compound of Formula (IIBp) 
wherein each symbol is as defined above, which is a compound of formula (IIB) wherein Raxe2x80x2 is halogen
A compound of the formula (IIBb) is kept with fluorine, chlorine, bromine, iodine, iodine monochloride, N-bromosuccinimide, N-iodosuccinimide and the like in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., acetic acid, methanol, ethanol, ethyl acetate, dioxane, benzene, toluene, xylene, diethyl ether, chloroform, 1,2-dichloroethane, an optionally mixed solvent therefrom and the like), at room temperature to 100xc2x0 C. for 10 min to 24 hr to give a compound of the formula (IIBp).
Method 34: Synthetic Method of Compound of Formula (IIBq) 
wherein Ar is aryl or heteroaryl and other symbols are as defined above, which is a compound of the formula (IIB) wherein Raxe2x80x2 is aryl or heteroaryl
A compound of the formula (IIBp) is kept with a compound of the formula (42)
Ar-Y xe2x80x83xe2x80x83(42)
wherein Y is dihydroxyboryl, diethylboryl, tributylstannyl, trimethylstannyl and the like and Ar is as defined above, and tetrakistriphenylphosphine palladium and the like, in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., methanol, ethanol, ethyl acetate, dioxane, benzene, toluene, xylene, diethyl ether, chloroform, 1,2-dichloroethane, an optionally mixed solvent therefrom and the like), at room temperature to 100xc2x0 C. for 10 min to 24 hr to give a compound of the formula (IIBq).
Method 35: Synthetic Method of Compound of Formula (IIBr) 
wherein R34 and R35 are the same or different and each is hydrogen, or alkyl having 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl and the like and other symbols are as defined above, which is a compound of the formula (IIB) wherein Raxe2x80x2 is aminoalkyl, monoalkylaminoalkyl or dialkylaminoalkyl
Of the compounds of the formula (IIB) wherein Raxe2x80x2 is hydroxyalkyl, a compound of the formula (IIBs) 
wherein each symbol is as defined above is kept with a compound of the formula (43) 
wherein R36 is methyl, ethyl, trifluoromethyl, phenyl, 4-methylphenyl and the like and Hal is as defined above or a compound of the formula (44) 
wherein R36 is as defined above, in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., benzene, toluene, xylene, chloroform, dichloroethane, pyridine, an optionally mixed solvent therefrom and the like), in the presence of an organic base, such as pyridine, triethylamine and the like, or an inorganic base, such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like, at room temperature to 170xc2x0 C. for 1 to 24 hr to give a compound of the formula (45) 
wherein each symbol is as defined above.
The obtained compound of the formula (45) is kept with a compound of the 
wherein each symbol is as defined above, in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., methanol, ethanol, dioxane, benzene, toluene, xylene, diethyl ether, chloroform, dichloroethane, an optionally mixed solvent therefrom and the like), at room temperature to 100xc2x0 C. for 10 min to 24 hr to give a compound of the formula (IIBr).
Method 36: Synthetic Method of Compound of Formula (IIBe) which is a Compound of Formula (IIB) wherein Raxe2x80x2 is Acyloxyalkyl or Acylaminoalkyl
For example, the above-mentioned compound of the formula (IIBd), which is a compound of the formula (IIB) wherein Raxe2x80x2 is aminoalkyl or monoalkylaminoalkyl, is kept with the above-mentioned compound of the formula (39) or (40), or ethyl formate, phenyl formate and the like, in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., benzene, toluene, xylene, chloroform, dichloroethane, pyridine, an optionally mixed solvent therefrom and the like), at room temperature to 100xc2x0 C. for 10 min to 24 hr to give a compound of the formula (IIBe).
Method 37: Synthetic Method of Compound of Formula (IIBe) 
wherein each symbol is as defined above, which is a compound of formula (IIB) wherein Raxe2x80x2 is nitro
For example, a compound of the formula (IIBb) is reacted with a suitable nitrating reagent, such as concentrated nitric acid-concentrated sulfuric acid, acetyl nitrate, nitronium tetrafluoroborate and the like, at 0xc2x0 C. to 100xc2x0 C. for 10 min to 24 hr to give a compound of the formula (IIBt).
Method 38: Synthetic Method of Compound of Formula (IIBu) 
wherein each symbol is as defined above, which is a compound of formula (IIB) wherein substituent on ring A is amino
A compound of the formula (IIBv) which is a compound of the formula (IIB) wherein the substituent on ring A is nitro 
wherein each symbol is as defined above, is kept with hydrogen in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., methanol, ethanol, ethyl acetate, dioxane, benzene, toluene, xylene, diethyl ether, chloroform, 1,2-dichloroethane, an optionally mixed solvent therefrom and the like), using palladium-activated carbon, palladium hydroxide, platinium oxide and the like as a catalyst, at 0xc2x0 C. to 100xc2x0 C. and normal pressure to 100 atm for 10 min to 24 hr, to give a compound of the formula (IIBu).
Method 39: Synthetic Method of Compound of Formula (IIBw) 
wherein Z is fluorine, chlorine, bromine, iodine or cyano and other symbols are as defined above, which is a compound of formula (IIB) wherein substituent on ring A is cyano or halogen
For example, a compound of the formula (IIBu) is diazotized in a suitable solvent, such as a solvent that does not adversely affect the reaction (e.g., water, diluted hydrochloric acid, and the like) using sodium nitrite and the like at xe2x88x9210xc2x0 C. to room temperature, and kept with fluoroboric acid, hydrogen fluoride-pyridine, sodium chloride, cuprous chloride, sodium bromide, cuprous bromide, sodium iodide, potassium iodide and the like at xe2x88x9210xc2x0 C. to 100xc2x0 C. to give a compound of the formula (IIBw).
When the compound obtained according to the above-mentioned method is to be purified as a salt of inorganic acid or organic acid, the following steps are taken. A compound of the formula (IA) or a compound of the formula (IB) is dissolved in a suitable solvent, such as methanol, ethanol, isopropyl alcohol, ethyl acetate, diethyl ether, diisopropyl ether, benzene, toluene, xylene, chloroform, methylene chloride and the like, an optionally mixed solvent therefrom and the like, and inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like or organic acid such as acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, ascorbic acid, maleic acid, citric acid, tartaric acid, fumaric acid and the like or a hydrate thereof is added. The resulting crystals were recrystallized from a suitable solvent, such as methanol, ethanol, isopropyl alcohol, ethyl acetate, diethyl ether, dhisopropyl ether, benzene, toluene, xylene, chloroform, methylene chloride, dichloroethane and the like or a mixed solvent thereof to give a salt of an inorganic acid, organic acid, hydrate or solvate of a compound of the formula (IA) or a compound of the formula (IB).
The obtained compound of the present invention can be purified by one or more methods selected from crystallization, chromatography, extraction and filtration. When the resulting purified compound is a racemate, a desired optically active compound can be separated by, for example, preparative recrystallzation from an optically active acid, or by passing the compound through a column packed with optically active carrier. The stereoisomer can be isolated by recrystallization, column chromatography and the like.
The compound of the formula (I), particularly (IA) and (IB), of the present invention obtained in the above-mentioned manner is useful as a novel antipsychotic agent which is effective for both the positive and negative symptoms of schizophrenia, which causes less side effects of extrapyramidal motor disorder and the like and which causes less serious side effects such as agranulocytosis and the like. The present invention compound (I), particularly (IA) and (IB), is useful as a therapeutic agent for Alzheimer""s disease and manic-depressive illness. The compounds of the formulas (IIA) and (IIB) are useful as important synthetic intermediates for the compounds of the formulas (IA) and (IB).
When the compound of the formula (I) is used as a pharmaceutical agent, the inventive compound is admixed with a pharmaceutically acceptable carrier (e.g., excipient, binder, disintegrator, corrective, corrigent, emulsifier), diluent, solubilizer and the like to give a pharmaceutical composition by a conventional method, which is formulated into tablet, capsule, granule, powder, syrup, suspension, solution, injection, infusion, deposit agent, suppository and the like and administered orally or parenterally.
When the tablets are used for oral administration, typically used carriers include sucrose, lactose, mannitol, maltitol, dextran, corn starch and the like, typical lubricants such as magnesium stearate, preservatives such as parabens, sorbins and the like, antioxidants such as ascorbic acid, xcex1-tocopherol, cystein and the like, disintegrators, binders and the like. When it is administered orally as capsules, effective diluents include lactose and dry corn starch. A liquid for oral use includes syrup, suspension, solution, emulsion and the like, which may contain typical inert diluent used in this field, such as water. In addition, sweeteners or flavors may be contained.
In the case of parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion and the like, the pH of the active ingredient solution is adequately adjusted, bufferized and sterilized. Examples of usable vehicle or solvent include distilled water, Ringer solution, isotonic brine and the like. For intravenous use, the total concentration of solute is adjusted to make the solution isotonic.
Suppositories can be produced by admixing with a drug and a suitable nonirritative excipient such as those that are solid at normal temperature but become liquid at the temperature in the intestine and melt in rectum to release the drug, such as cocoa butter and polyethylene glycols, and the like.
The dose is determined depending on age, body weight, administration time, administration method, combination of drugs, the level of condition for which a patient is undergoing therapy, and other factors. The compound of the present invention, optical isomers thereof and pharmaceutically acceptable salts thereof are low toxic and can be used safely. While the daily dose varies depending on the conditions and body weight of patients, the kdnd of compound, administration route and the like, in the case of oral use, it is about 0.01-300 mg/person/day, preferably 0.1-100 mg/person/day, in the case of parenteral use, it is desirably about 0.01-50 mg/person/day, preferably 0.01-10 mg/person/day for subcutaneous injection, intravenous injection, intramuscular injection and intrarectal injection.
The present invention is explained in more detail in the following by way of Starting Material Synthesis Examples, Examples and Experimental Examples that do not limit the present invention in any way.